Heart Health - TOCOTRIENOL Tocotrienol.org

Published Human Studies/ Cohort Studies
Article	Study objective/ findings
Short term effects of palm-tocotrienol and palm-carotenes on vascular function and cardiovascular disease risk: A randomised controlled trial. Stonehouse. W., et.al (2016). Atheosclerosis.	The effects of palm-tocotrienols (TRF- 80) and palm-carotene (CC-60) supplementation on vascular function and cardiovascular disease (CVD) risk factors in adults at increased risk of impaired vascular function are examined. CC-60 and TRF-80 supplementation increased bioavailability of palm-based carotenes and tocotrienols but had no effects, superior or detrimental, on vascular function or CVD risk factors.
Safety and lipid-altering efficacy of a new omega-3 fatty acid and antioxidant-containing medical food in men and women with elevated triacylglycerols. Maki, K.C., et.al (2015). Prostaglandins Leukot Essent Fatty Acids.	This randomized, double-blind, placebo-controlled multi-center trial investigated the lipid-altering effects of a medical food (PDL-0101) providing 1.8 g/d eicosapentaenoic acid; 12 mg/d astaxanthin, a marine algae-derived carotenoid; and 100 mg/d tocopherol-free gamma/delta tocotrienols enriched with geranylgeraniol, extracted from annatto, on triacylglycerols (TAG), other lipoprotein lipids, and oxidized low-density lipoprotein (LDL) in 102 subjects with TAG 150–499 mg/dL (1.69–5.63 mmol/L) and LDL cholesterol (LDL-C) ≥70 mg/dL (1.81 mmol/L). These results demonstrate that PDL-0101 is an effective medical food for the management of elevated TAG.
A combination of palm oil tocotrienols and citrus peel polymethoxylated flavones does not influence elevated LDL cholesterol and high-sensitivity C-reactive protein levels. Schuchardt, J.P., et.al (2015). Eur J Clin Nutr.	This study investigated low-density lipoprotein-cholesterol (LDL-C) – and high-sensitivity C-reactive protein (hsCRP)-reducing effects of combined TT-PMF treatment in low doses in hypercholesterolemic individuals with subclinical inflammation. PMF-TT supplements had no effect beyond that of placebo on elevated LDL-C and hsCRP levels
Supplementation with tocotrienol-rich fraction alters the plasma levels of Apolipoprotein (A-I) precursor, Apolipoprotein E precursor, and C-reactive protein precursor from young and old individuals. Heng, E.C., et.al. (2013). Eur J Nutr.	The plasma proteins that changed in expression following tocotrienol-rich fraction (TRF) supplementation within two different age groups has been identified. TRF appears to not only affect plasma levels of tocopherols and tocotrienols, but also the levels of plasma proteins. The identity of these proteins may provide insights into how TRF exerts its beneficial effects. They may also be potentially developed into biomarkers for the study of the effects and effectiveness of TRF supplementation.
Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients. Daud, Z.A., et.al (2013). Vasc Health Risk Manag.	Chronic hemodialysis patients experience accelerated atherosclerosis contributed to by dyslipidemia, inflammation, and an impaired antioxidant system. Vitamin E tocotrienols possess anti-inflammatory and antioxidant properties. However, the impact of dietary intervention with Vitamin E tocotrienols is unknown in this population. TRF supplementation improved lipid profiles in this study of maintenance hemodialysis patients. A multi-centered trial is warranted to confirm these observations.
Suppression of nitric oxide production and cardiovascular risk factors in healthy seniors and hypercholestrolemic subjects by a combination of polyphenols and vitamins Qureshi, A. A., et.al (2012). J Clin Exp Cardiolog.	This study determines whether serum nitric oxide (NO) levels increase with age in humans, and whether the combined cholesterol-lowering and inflammation-reducing properties of resveratrol, pterostilbene, Morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid would reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes. Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.
Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study. Chin, S.F, et.al (2011). Nutr Metab (Lond)	The effects of Tocotrienol Rich Fraction (TRF) supplementation on lipid profile and oxidative status in healthy older individuals at a dose of 160 mg/day for 6 months are evaluated. The observed improvement of plasma cholesterol, AGE(advanced glycation end product) and antioxidant vitamin levels as well as the reduced protein damage may indicate a restoration of redox balance after TRF supplementation, particularly in individuals over 50 years of age.
Effect of Mixed-Tocotrienols in Hypercholesterolemic Subjects Yuen, K.H., et.al (2011). Functional Foods in Health and Disease.	A randomized, double-blind, parallel group study was conducted to investigate the cholesterol lowering activity of tocotrienols. Supplementation with mixed tocotrienols at dose of 300 mg per day resulted in the lowering of the serum total and LDL cholesterol levels after 5 months of supplementation.
Gamma delta tocotrienols reduce hepatic triglyceride synthesis and VLDL secretion. Zaiden, N., et.al (2010). J of Atherosclerosis and Thrombosis.	The lipid-lowering effects of gamma-delta tocotrienol were investigated using HepG2 liver cell line, hypercholesterolemic mice and borderline-high cholesterol patients. Reduction in triglycerides synthesis and transport may be the primary benefit caused by ingesting gamma, delta-tocotrienol in human.
Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects. James, M., et.al (2007). Altern Ther Health Med.	To examine the effect of these nutrients in combination on blood levels of cholesterol and related cardiovascular disease risk factors. Daily treatment with S significantly improved cardiovascular parameters compared to P in all groups. Significant reductions were shown in total cholesterol (20%-30%), LDL (19%-27%), apolipoprotein B (21%), and triglycerides (24%-34%). HDL levels remained unchanged in G1 and G2 but increased 4% (nonsignificant) in G3 and was accompanied by a significant increase in apolipoprotein A1 (5%).
Dose dependent elevation of plasma tocotrienol levels and its effects on arterial compliance, plasma total antioxidant status, and lipid profile in healthy humans supplemented with tocotrienol rich vitamin E. Rasool, A.H.G., et.al (2006). J Nutr Sci. Vitaminol.	The effects of 3 doses of TRF vitamin E on plasma tocotrienol isomer concentration, arterial compliance, plasma total antioxidant status (TAS), aortic systolic blood pressure (ASBP), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in healthy males. Treatment significantly increased alpha-, delta- and gamma- tocotrienol concentrations but did not significantly affect arterial compliance, plasma TAS, serum TC or LDL-C levels in normal subjects.
The therapeutic impacts of tocotrienols in type 2 diabetic patients with hyperlipidemia. Baliarsingh, S., et.al (2005). Atherosclerosis .	The therapeutic impacts of tocotrienols on serum and lipoprotein lipid levels in type 2 diabetic patients. Daily intake of dietary TRF by type 2 diabetics will be useful in the prevention and treatment of hyperlipidemia and atherogenesis.
Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia Mustard, V. A., et.al (2002). Am J Clin Nutr.	The relative effect of tocotrienol supplements of different compositions (mixed – plus -, high -, or P25-complex tocotrienol) on blood lipids, fasting blood glucose, and the excretion of 8-iso-prostaglandin F2, a measure of oxidative stress, in healthy hypercholesterolemic men and women is studied. Supplementation with tocotrienols from 3 commercially available sources has no beneficial effect on key cardiovascular disease risk factors in highly compliant adults with elevated blood lipid concentrations.
Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters. Raederstorff, D., et.al (2002). Ann Nutr Metab.	The effects of a 4-week dietary supplement of either gamma-tocotrienol or a mixture of tocotrienols (mix-T3) on the plasma lipid profile in hamsters receiving a high fat diet. This study provides further evidence that tocotrienols lower total cholesterol and low density lipoprotein plasma levels in hamsters and that gamma-tocotrienol is a more potent agent than a mixture of tocotrienols.
Synergistic effect of tocotrienol-rich fraction (TRF-25) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans. Qureshi, A.A., et.al (2001). J Nutr Biochem.	Tocotrienols exert hypocholesterolemic action in humans and animals. Lovastatin is widely used for that purpose. In the present study, the increased effectiveness of low doses of tocotrienols (TRF(25)) as hypocholesterolemic agents might be due to a minimum conversion to alpha-tocopherol. The report also describes in vivo the conversion of gamma-[4-3H]-, and [14C]-desmethyl (d-P(21)-T3) tocotrienols to alpha-tocopherol.
Studies of LDL oxidation following alpha-, gamma- or delta-tocotrienyl acetate supplementation of hypercholesterolemic humans O’Byrne D., et.al (2000). Free Radic Biol Med.	The investigation whether daily supplements of placebo, or alpha-, gamma-, or delta- (alpha-, gamma-, or delta-) tocotrienyl acetates would alter serum cholesterol or LDL oxidative resistance in hypercholesterolemics in a double-blind placebo controlled study. This study demonstrates that: (i) tocotrienyl acetate supplements are hydrolyzed, absorbed, and detectable in human plasma; (ii) tocotrienyl acetate supplements do not lower cholesterol in hypercholesterolemic subjects on low-fat diets; and (iii) alpha-T3 may be potent in decreasing LDL oxidizability.
Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Torneo, A.C., et.al (1995). Lipids.	The antioxidant properties of Palm Vitee, a gamma-tocotrienol-, and alpha-tocopherol enriched fraction of palm oil, in patients with carotid atherosclerosis are investigated. These findings suggest that antioxidants, such as tocotrienols, may influence the course of carotid atherosclerosis.
Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (Palmvitee). Qureshi, A.A., et.al (1991). Am J Clin Nutr.	This study assesses the effect of TRF as dietary supplement in hypercholestrelemic human subjects. This indicates that gamma-T3 maybe the most potent cholesterol inhibitor in palmvitee capsules.
Effect of a palm-oil-vitamin E concentrate on the serum and lipoprotein lipids in humans. Tan D.T., et.al (1991). Am J Clin Nutr.	The effect of a capsulated palm-oil-vitamin E concentrate (palmvitee) on human serum and lipoprotein lipids was assessed. Our results show that the palmvitee has a hypocholesterolemic effect.

Published Human Studies/ Cohort Studies

Article

Study objective/ findings

Short term effects of palm-tocotrienol and palm-carotenes on vascular function and cardiovascular disease risk: A randomised controlled trial.

Stonehouse. W., et.al (2016). Atheosclerosis.

The effects of palm-tocotrienols (TRF- 80) and palm-carotene (CC-60) supplementation on vascular function and cardiovascular disease (CVD) risk factors in adults at increased risk of impaired vascular function are examined. CC-60 and TRF-80 supplementation increased bioavailability of palm-based carotenes and tocotrienols but had no effects, superior or detrimental, on vascular function or CVD risk factors.

Safety and lipid-altering efficacy of a new omega-3 fatty acid and antioxidant-containing medical food in men and women with elevated triacylglycerols.

Maki, K.C., et.al (2015). Prostaglandins Leukot Essent Fatty Acids.

This randomized, double-blind, placebo-controlled multi-center trial investigated the lipid-altering effects of a medical food (PDL-0101) providing 1.8 g/d eicosapentaenoic acid; 12 mg/d astaxanthin, a marine algae-derived carotenoid; and 100 mg/d tocopherol-free gamma/delta tocotrienols enriched with geranylgeraniol, extracted from annatto, on triacylglycerols (TAG), other lipoprotein lipids, and oxidized low-density lipoprotein (LDL) in 102 subjects with TAG 150–499 mg/dL (1.69–5.63 mmol/L) and LDL cholesterol (LDL-C) ≥70 mg/dL (1.81 mmol/L). These results demonstrate that PDL-0101 is an effective medical food for the management of elevated TAG.

A combination of palm oil tocotrienols and citrus peel polymethoxylated flavones does not influence elevated LDL cholesterol and high-sensitivity C-reactive protein levels.

Schuchardt, J.P., et.al (2015). Eur J Clin Nutr.

This study investigated low-density lipoprotein-cholesterol (LDL-C) – and high-sensitivity C-reactive protein (hsCRP)-reducing effects of combined TT-PMF treatment in low doses in hypercholesterolemic individuals with subclinical inflammation. PMF-TT supplements had no effect beyond that of placebo on elevated LDL-C and hsCRP levels

Supplementation with tocotrienol-rich fraction alters the plasma levels of Apolipoprotein (A-I) precursor, Apolipoprotein E precursor, and C-reactive protein precursor from young and old individuals.

Heng, E.C., et.al. (2013). Eur J Nutr.

The plasma proteins that changed in expression following tocotrienol-rich fraction (TRF) supplementation within two different age groups has been identified. TRF appears to not only affect plasma levels of tocopherols and tocotrienols, but also the levels of plasma proteins. The identity of these proteins may provide insights into how TRF exerts its beneficial effects. They may also be potentially developed into biomarkers for the study of the effects and effectiveness of TRF supplementation.

Vitamin E tocotrienol supplementation improves lipid profiles in chronic hemodialysis patients.

Daud, Z.A., et.al (2013). Vasc Health Risk Manag.

Chronic hemodialysis patients experience accelerated atherosclerosis contributed to by dyslipidemia, inflammation, and an impaired antioxidant system. Vitamin E tocotrienols possess anti-inflammatory and antioxidant properties. However, the impact of dietary intervention with Vitamin E tocotrienols is unknown in this population. TRF supplementation improved lipid profiles in this study of maintenance hemodialysis patients. A multi-centered trial is warranted to confirm these observations.

Suppression of nitric oxide production and cardiovascular risk factors in healthy seniors and hypercholestrolemic subjects by a combination of polyphenols and vitamins

Qureshi, A. A., et.al (2012). J Clin Exp Cardiolog.

This study determines whether serum nitric oxide (NO) levels increase with age in humans, and whether the combined cholesterol-lowering and inflammation-reducing properties of resveratrol, pterostilbene, Morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid would reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes. Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study.

Chin, S.F, et.al (2011). Nutr Metab (Lond)

The effects of Tocotrienol Rich Fraction (TRF) supplementation on lipid profile and oxidative status in healthy older individuals at a dose of 160 mg/day for 6 months are evaluated. The observed improvement of plasma cholesterol, AGE(advanced glycation end product) and antioxidant vitamin levels as well as the reduced protein damage may indicate a restoration of redox balance after TRF supplementation, particularly in individuals over 50 years of age.

Effect of Mixed-Tocotrienols in Hypercholesterolemic Subjects

Yuen, K.H., et.al (2011). Functional Foods in Health and Disease.

A randomized, double-blind, parallel group study was conducted to investigate the cholesterol lowering activity of tocotrienols. Supplementation with mixed tocotrienols at dose of 300 mg per day resulted in the lowering of the serum total and LDL cholesterol levels after 5 months of supplementation.

Gamma delta tocotrienols reduce hepatic triglyceride synthesis and VLDL secretion.

Zaiden, N., et.al (2010). J of Atherosclerosis and Thrombosis.

The lipid-lowering effects of gamma-delta tocotrienol were investigated using HepG2 liver cell line, hypercholesterolemic mice and borderline-high cholesterol patients. Reduction in triglycerides synthesis and transport may be the primary benefit caused by ingesting gamma, delta-tocotrienol in human.

Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects.

James, M., et.al (2007). Altern Ther Health Med.

To examine the effect of these nutrients in combination on blood levels of cholesterol and related cardiovascular disease risk factors. Daily treatment with S significantly improved cardiovascular parameters compared to P in all groups. Significant reductions were shown in total cholesterol (20%-30%), LDL (19%-27%), apolipoprotein B (21%), and triglycerides (24%-34%). HDL levels remained unchanged in G1 and G2 but increased 4% (nonsignificant) in G3 and was accompanied by a significant increase in apolipoprotein A1 (5%).

Dose dependent elevation of plasma tocotrienol levels and its effects on arterial compliance, plasma total antioxidant status, and lipid profile in healthy humans supplemented with tocotrienol rich vitamin E.

Rasool, A.H.G., et.al (2006). J Nutr Sci. Vitaminol.

The effects of 3 doses of TRF vitamin E on plasma tocotrienol isomer concentration, arterial compliance, plasma total antioxidant status (TAS), aortic systolic blood pressure (ASBP), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in healthy males. Treatment significantly increased alpha-, delta- and gamma- tocotrienol concentrations but did not significantly affect arterial compliance, plasma TAS, serum TC or LDL-C levels in normal subjects.

The therapeutic impacts of tocotrienols in type 2 diabetic patients with hyperlipidemia.

Baliarsingh, S., et.al (2005). Atherosclerosis

The therapeutic impacts of tocotrienols on serum and lipoprotein lipid levels in type 2 diabetic patients. Daily intake of dietary TRF by type 2 diabetics will be useful in the prevention and treatment of hyperlipidemia and atherogenesis.

Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia

Mustard, V. A., et.al (2002). Am J Clin Nutr.

The relative effect of tocotrienol supplements of different compositions (mixed – plus -, high -, or P25-complex tocotrienol) on blood lipids, fasting blood glucose, and the excretion of 8-iso-prostaglandin F2, a measure of oxidative stress, in healthy hypercholesterolemic men and women is studied. Supplementation with tocotrienols from 3 commercially available sources has no beneficial effect on key cardiovascular disease risk factors in highly compliant adults with elevated blood lipid concentrations.

Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters.

Raederstorff, D., et.al (2002). Ann Nutr Metab.

The effects of a 4-week dietary supplement of either gamma-tocotrienol or a mixture of tocotrienols (mix-T3) on the plasma lipid profile in hamsters receiving a high fat diet. This study provides further evidence that tocotrienols lower total cholesterol and low density lipoprotein plasma levels in hamsters and that gamma-tocotrienol is a more potent agent than a mixture of tocotrienols.

Synergistic effect of tocotrienol-rich fraction (TRF-25) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans.

Qureshi, A.A., et.al (2001). J Nutr Biochem.

Tocotrienols exert hypocholesterolemic action in humans and animals. Lovastatin is widely used for that purpose. In the present study, the increased effectiveness of low doses of tocotrienols (TRF(25)) as hypocholesterolemic agents might be due to a minimum conversion to alpha-tocopherol. The report also describes in vivo the conversion of gamma-[4-3H]-, and [14C]-desmethyl (d-P(21)-T3) tocotrienols to alpha-tocopherol.

Studies of LDL oxidation following alpha-, gamma- or delta-tocotrienyl acetate supplementation of hypercholesterolemic humans

O’Byrne D., et.al (2000). Free Radic Biol Med.

The investigation whether daily supplements of placebo, or alpha-, gamma-, or delta- (alpha-, gamma-, or delta-) tocotrienyl acetates would alter serum cholesterol or LDL oxidative resistance in hypercholesterolemics in a double-blind placebo controlled study. This study demonstrates that: (i) tocotrienyl acetate supplements are hydrolyzed, absorbed, and detectable in human plasma; (ii) tocotrienyl acetate supplements do not lower cholesterol in hypercholesterolemic subjects on low-fat diets; and (iii) alpha-T3 may be potent in decreasing LDL oxidizability.

Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis.

Torneo, A.C., et.al (1995). Lipids.

The antioxidant properties of Palm Vitee, a gamma-tocotrienol-, and alpha-tocopherol enriched fraction of palm oil, in patients with carotid atherosclerosis are investigated. These findings suggest that antioxidants, such as tocotrienols, may influence the course of carotid atherosclerosis.

Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (Palmvitee).

Qureshi, A.A., et.al (1991). Am J Clin Nutr.

This study assesses the effect of TRF as dietary supplement in hypercholestrelemic human subjects. This indicates that gamma-T3 maybe the most potent cholesterol inhibitor in palmvitee capsules.

Effect of a palm-oil-vitamin E concentrate on the serum and lipoprotein lipids in humans.

Tan D.T., et.al (1991). Am J Clin Nutr.

The effect of a capsulated palm-oil-vitamin E concentrate (palmvitee) on human serum and lipoprotein lipids was assessed. Our results show that the palmvitee has a hypocholesterolemic effect.

In vivo/ Animal Studies
Article	Study objectives/ Findings
High purity tocotrienols attenuate atherosclerotic lesion formation in apoE-KO mice. Shibata, A., et.al (2017). J Nutr Biochem.	Previous studies have demonstrated that tocotrienol (T3) has antiatherogenic effects. However, the T3 preparations used in those studies contained considerable amounts of tocopherol (Toc), which might affect the biological activity of T3. There is little information on the effect of highly purified T3 on atherosclerosis formation. This study investigated the effect of high-purity T3 on atherosclerotic lesion formation and the underlying mechanisms. Male apolipoprotein E knockout (apoE-KO) mice were fed a cholesterol-containing diet either alone or supplemented with T3 concentrate (Toc-free T3) or with α-Toc for 12 weeks. ApoE-KO mice fed the 0.2% T3-supplemented diet showed reduced atherosclerotic lesion formation in the aortic root. The 0.2% T3 diet induced Slc27a1 and Ldlr gene expression levels in the liver, whereas the α-Toc-supplemented diet did not affect those expression levels. T3 was predominantly deposited in fat tissue in the T3 diet-fed mice, whereas α-Toc was preferentially accumulated in liver in the α-Toc diet-fed mice. Considered together, these data demonstrate that dietary T3 exerts anti-atherosclerotic effect in apoE-KO mice. The characteristic tissue distribution and biological effects of T3, that are substantially different from those of Toc, may contribute to the antiatherogenic properties of T3.
Anti-inflammatory γ- and δ-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats. Wong, W.Y., et.al (2017). Eur J Nutr	This study tested the hypothesis that γ- and δ-tocotrienols are more effective than α-tocotrienol and α-tocopherol in attenuating the signs of diet-induced metabolic syndrome in rats. In rats, δ-tocotrienol improved inflammation, heart structure and function, and liver structure and function, while γ-tocotrienol produced more modest improvements, with minimal changes with α-tocotrienol and α-tocopherol. The most important mechanism of action is likely to be reduction in organ inflammation.
Atheroprotective effects of pure tocotrienol supplementation in the treatment of rabbits with experimentally induced early and established atherosclerosis. Rahman, T. A., et.al (2016). Food Nutr Res.	The atheroprotective properties of T3 in early and established atherosclerosis rabbits is established. These findings suggest the possible atheroprotective role T3 plays as an adjunct supplementation to standard treatment in the prevention of coronary artery disease.
Tocotrienol-Rich Tocomin Attenuates Oxidative Stress and Improves Endothelium-Dependent Relaxation in Aortae from Rats Fed a High-Fat Western Diet. Ali, S.F., et.al (2016). Front Cardiovasc Med.	The role of whether Tocomin treatment (natural palm mixed-tocotrienol complex) preserves endothelial function in aortae isolated from rats fed a high-fat diet known to cause oxidative stress was investigated. The beneficial actions of tocomin in this diet-induced model of obesity suggest that it may have potential to be used as a therapeutic agent to prevent vascular disease in obesity.
Effects of Late Administration of Pentoxifylline and Tocotrienols in an Image-Guided Rat Model of Localized Heart Irradiation Sridharan, V., et.al (2013). PLoS One.	This study examined the effects of pentoxifylline (PTX) alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation.
Palm Tocotrienol-Rich Fraction Improves Vascular Proatherosclerotic Changes in Hyperhomocysteinemic Rats Norsidah, K-Z., et.al (2013). Evid Based Complement Alternat Med.	This study investigated the effects of palm tocotrienol-rich fraction (TRF) on aortic proatherosclerotic changes in rats fed with a high methionine diet. Palm TRF was comparable to folate in reducing high methionine diet-induced plasma hyperhomocysteinemia, aortic oxidative stress, and inflammatory changes in rats.
Suppression of nitric oxide production and cardiovascular risk factors in healthy seniors and hypercholesterolemic subjects by a combination of polyphenols and vitamains Qureshi, A.A, et.al (2012). J Clin Exp Cardiolog.	To determine whether serum nitric oxide (NO) levels increase with age in humans, and whether the combined cholesterol-lowering and inflammation-reducing properties of resveratrol, pterostilbene, Morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid would reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes. Serum NO levels are elevated in elderly humans compared to children or young adults. Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.
δ-Tocotrienol and quercetin reduce serum levels of nitric oxide and lipid parameters in female chickens Qureshi, A.A., et.al (2011). Lipids Health Dis.	Chronic, low-grade inflammation provides a link between normal ageing and the pathogenesis of age-related diseases. A series of in vitro tests confirmed the strong anti-inflammatory activities of known inhibitors of NF-κB activation (δ-tocotrienol, quercetin, riboflavin, (-) Corey lactone, amiloride, and dexamethasone). δ-Tocotrienol also suppresses β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase activity (the rate-limiting step in de novo cholesterol synthesis), and concomitantly lowers serum total and LDL cholesterol levels. We evaluated these compounds in an avian model anticipating that a dietary additive combining δ-tocotrienol with quercetin, riboflavin, (-) Corey lactone, amiloride, or dexamethasone would yield greater reductions in serum levels of total cholesterol, LDL-cholesterol and inflammatory markers (tumor necrosis factor-α [TNF-α], and nitric oxide [NO]), than that attained with the individual compounds.
Tocotrienol enriched palm oil prevents atherosclerosis through modulating the activities of peroxisome proliferators-activated receptors. Li, F. et.al (2010). Atherosclerosis.	Palm oil is enriched in vitamin E in the form of alpha-, gamma-, and delta-tocotrienols. Dietary tocotrienol supplements have been shown to prevent atherosclerosis development in patients and preclinical animal models. However, the mechanistic basis for this health beneficial effect is not well established. Peroxisome proliferator-activated receptors alpha, gamma, and delta (PPARalpha, PPARgamma, and PPARdelta) are ligand regulated transcription factors that play essential preventive roles in the development of atherosclerosis through regulating energy metabolism and inflammation. In this study, we presented data that the tocotrienol rich fraction (TRF) of palm oil activated PPARalpha, PPARgamma, and PPARdelta in reporter based assays. Importantly, TRF attenuated the development of atherosclerosis in ApoE-/- mice through inducing PPAR target gene liver X receptor alpha (LXRalpha) and its down-stream target genes apolipoproteins and cholesterol transporters, suggesting that modulating the activities of PPARs is a key aspect of the in vivo action of tocotrienols.
Comparative study of the effect of tocotrienols and tocopherols on fasting serum lipid profiles in patients with mild hypercholesterolaemia: A preliminary report. Ajuluchukwu, J.N., et.al (2007). Niger Postgrad Med. J	This study examines the effects of tocotrienols on serum lipids. This study adds to existing evidence of the favorable effect of tocotrienols on total cholesterol and LDL-C. However, the results need further clarification.
Proposed mechanisms of red palm oil induced cardioprotection in a model of hyperlipidaemia in rat Esterhuyse. J.S., et.al (2006). Prostaglandins Leukot Essent Fatty Acids.	The effects of dietary red palm oil (RPO) containing fatty acids, carotonoids, tocopherols and tocotrienols on myocardial ischaemic tolerance and NO-cGMP pathway function in the rat. Wistar rats were fed a standard rat chow+/-RPO, or a standard rat chow+cholesterol+/-RPO diet. These data suggest that dietary RPO may improve myocardial ischaemic tolerance by increasing bioavailability of NO and improving NO-cGMP signaling in the heart.
Dose-response impact of various tocotrienols on serum lipid parameters in 5-week old female chickens. Yu, S.G., et.al (2006). Lipids.	The cholesterol-suppressive action of the tocotrienol-rich-fraction (TRF) of palm oil may be due to the effect of its constituent tocotrienols on beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase activity. The tocotrienols, modulate HMG-CoA reductase activity via a post-transcriptional mechanism. As a consequence small doses (5-200 ppm) of TRF-supplemented diets fed to experimental animals lower serum cholesterol levels. Alpha-Tocopherol did not affect total or LDL-cholesterol levels. Supplemental alpha-tocotrienol within the 50-500 ppm range produced a dose-response lowering of total (17%) and LDL (33%) cholesterol levels. The more potent gamma and delta isomers yielded dose-response (50-2,000 ppm) reductions of serum total (32%) and LDL (66%) cholesterol levels. HDL cholesterol levels were minimally impacted by the tocotrienols; as a result, the HDL/LDL cholesterol ratios were markedly improved (123-150%) by the supplements. Serum triglyceride levels were significantly lower in sera of pullets receiving the higher supplements. The safe dose of various tocotrienols for human consumption might be 200-1000 mg/d based on this study.
Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes Samarjit, D., et.al (2005). APS Journals.	The present study was designed to determine whether tocotrienol has a direct cardioprotective role. The results of this study support a role for c-Src in postischemic cardiac injury and dysfunction and demonstrate direct cardioprotective effects of TRF. The cardioprotective properties of TRF appear to be due to inhibition of c-Src activation and proteasome stabilization.
Hypolipidemic and antioxidant properties of tocotrienol rich fraction isolated from rice bran oil in experimentally induced hyperlipidemic rats. Minhajuddin, M., et.al (2005). Food Chem Toxicol.	A dose-dependent hypolipidemic and antioxidant effect of tocotrienol rich fraction (TRF) isolated from rice bran oil on experimentally induced hyperlipidemic rats was investigated. These results suggest that TRF supplementation has significant health benefits through the modulation of physiological functions that include various atherogenic lipid profiles and antioxidants in hypercholesterolemia.
Suppression of 7,12-dimethylbenz[alpha]anthracene-induced carcinogenesis and hypercholesterolaemia in rats by tocotrienol-rich fraction isolated from rice bran oil. Iqbal, J., et.al (2003). Eur J Cancer Prev.	The anti-tumour and anti-cholesterol impacts of tocotrienol-rich fraction (TRF) were investigated in rats treated with the chemical carcinogen 7,12-dimethylbenz [alpha]anthracene (DMBA), which is known to induce mammary carcinogenesis and hypercholesterolaemia. Results indicate that TRF has potent anti-cancer and anti-cholesterol effects in rats.
Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters. Raederstorff, D., et.al (2002). Ann Nutr Metab.	The effects of a 4-week dietary supplement of either gamma-tocotrienol (86% gamma-T3) or a mixture of tocotrienols (29.5% alpha-T3, 3.3% beta-T3, 41.4% gamma-T3, 0.1% delta-T3: mix-T3) on the plasma lipid profile in hamsters receiving a high fat diet were investigated. This study provides further evidence that tocotrienols lower total cholesterol and low density lipoprotein plasma levels in hamsters and that gamma-tocotrienol is a more potent agent than a mixture of tocotrienols.
Dose-dependent cholesterolemic activity of tocotrienols. Khor, H. et.al (2002). J Nutr.	The effect of tocotrienols and alpha-tocopherol on the activities of HMG CoA reductase and cholesterol 7 a-hydroxylase was investigated. Our results showed that the effects of tocotrienols and a-tocopherol on the activities of both the enzymes were dose-dependent. At low dosages, both tocotrienols and a-tocopherol exhibited an inhibitory effect on both the enzymes. Moreover, tocotrienols were a much stronger inhibitors than a-tocopherol. At high dosages, on the other hand, tocotrienols and a-tocopherol showed opposite effects on the enzymes. While tocotrienols continued to exhibit an inhibitory effect, a-tocopherol actually exhibited a stimulatory effect on both the enzymes. A possible explanation for this observation is suggested.
The combined effects of novel tocotrienols and lovastatin on lipid metabolism in chickens. Qureshi & Peterson (2001). Atheroschlerosis.	Both lovastatin (a fungal product) and a tocotrienol rich fraction (TRF(25), a mixture of tocols isolated from stabilized and heated rice bran containing desmethyl [d-P(21)-T3] and didesmethyl [d-P(25)-T3] tocotrienols) are potent hypocholesterolemic agents, although they suppress cholesterol biosynthesis by different mechanisms. To determine additive and/or synergistic effects of both agents, chickens were fed diets supplemented with 50 ppm TRF(25) or d-P(25)-T3 in combination with 50 ppm lovastatin for 4 weeks. The effects, however, of the d-P(25)-T3/lovastatin combination were no greater than that of d-P(25)-T3 alone, possibly indicating that d-P(25)-T3 produced a maximum cholesterol lowering effect at the concentration used.
Novel Tocotrienols of Rice Bran Suppress Cholesterogenesis in Hereditary Hypercholesterolemic Swine Qureshi, A.A., et.al (2001). Am Society for Nutritional Sc.	The effects of novel tocotrienols on lipid metabolism in swine expressing hereditary hypercholesterolemia is evaluated. This persistent effect may have resulted from the high tocotrienol levels in blood of the treatment groups, suggesting that the conversion of tocotrienols to tocopherols may not be as rapid as was reported in chickens and humans.
Tocotrienols Regulate Cholesterol Production in Mammalian Cells bv Post-transcriptional Suppression of 3-Hydroxy-3-methylglutarylCoenzyme A Reductase Parker, R.A., et.al (1993). J of Biol Chem.	Tocotrienols are natural farnesylated analogues of tocopherols which decrease hepatic cholesterol production and reduce plasma cholesterol levels in animals. For several cultured cell types, incubation with y-tocotrienol inhibited the rate of [‘%]acetate but not mevalonate incorporation into cholesterol in a concentration- and time-dependent manner, with 50% inhibition at -2 HM and maximum -80% inhibition observed within 6 h in HepG2 cells. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase total activity and protein levels assayed by Western blot were reduced concomitantly with the decrease in cholesterol synthesis. In HepG2 cells, y-tocotrienol suppressed reductase despite strong blockade by inhibitors at several steps in the pathway, suggesting that isoprenoid flux is not required for the regulatory effect. HMG-CoA reductase protein synthesis rate was moderately diminished (67% of control), while the degradation rate was increased 2.4-fold versus control (t1,2 declined from 3.73 to 1.59 h) as judged by [3SS]methionine pulse-chase/immunoprecipitation analysis of HepG2 cells treated with 10 PM y-tocotrienol. Under these conditions, the decrease in reductase protein levels greatly exceeded the minor decrease in mRNA (23 versus 76% of control, respectively), and the low density lipoprotein receptor protein was augmented. In contrast, 25-hydroxycholesterol strongly cosuppressed HMG-CoA reductase protein and mRNA levels and the low density lipoprotein receptor protein. Thus, tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMG-CoA reductase, and appear to specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative non-sterol isoprenoid regulators derived from mevalonate.
Tocotrienol and fatty acid composition of barley oil and their effects on lipid metabolism. Wang, L., et.al (1993). Plant Foods Hum Nutr.	Barley oil was extracted with hexane from the grain of a high oil waxy hull-less barley. Twelve male broiler chicks were fed corn-based diets with either 10% barley oil, 10% corn oil or 10% margarine ad libitum for ten days. These data suggest that alpha-tocotrienol and polyunsaturated fatty acids are hypocholesterolemic components in barley oil.
Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias. Qureshi, A.A., et.al (1991). Am J Clin Nutr.	Normolipemic and genetically hypercholesterolemic pigs of defined lipoprotein genotype were fed a standard diet supplemented with 50 micrograms/g tocotrienol-rich fraction (TRF) isolated from palm oil. Hypercholesterolemic pigs fed the TRF supplement showed a 44% decrease in total serum cholesterol, a 60% decrease in low-density-lipoprotein (LDL)-cholesterol, and significant decreases in levels of apolipoprotein B (26%), thromboxane-B2 (41%), and platelet factor 4 (PF4; 29%). The declines in thromboxane B2 and PF4 suggest that TRF has a marked protective effect on the endothelium and platelet aggregation. The effect of the lipid-lowering diet persisted only in the hypercholesterolemic swine after 8 wk feeding of the control diet. These results support observations from previous studies on lowering plasma cholesterol in animals by tocotrienols, which are naturally occurring compounds in grain and palm oils and may have some effect on lowering plasma cholesterol in humans.

In vivo/ Animal Studies

Article

Study objectives/ Findings

High purity tocotrienols attenuate atherosclerotic lesion formation in apoE-KO mice.

Shibata, A., et.al (2017). J Nutr Biochem.

Previous studies have demonstrated that tocotrienol (T3) has antiatherogenic effects. However, the T3 preparations used in those studies contained considerable amounts of tocopherol (Toc), which might affect the biological activity of T3. There is little information on the effect of highly purified T3 on atherosclerosis formation. This study investigated the effect of high-purity T3 on atherosclerotic lesion formation and the underlying mechanisms. Male apolipoprotein E knockout (apoE-KO) mice were fed a cholesterol-containing diet either alone or supplemented with T3 concentrate (Toc-free T3) or with α-Toc for 12 weeks. ApoE-KO mice fed the 0.2% T3-supplemented diet showed reduced atherosclerotic lesion formation in the aortic root. The 0.2% T3 diet induced Slc27a1 and Ldlr gene expression levels in the liver, whereas the α-Toc-supplemented diet did not affect those expression levels. T3 was predominantly deposited in fat tissue in the T3 diet-fed mice, whereas α-Toc was preferentially accumulated in liver in the α-Toc diet-fed mice. Considered together, these data demonstrate that dietary T3 exerts anti-atherosclerotic effect in apoE-KO mice. The characteristic tissue distribution and biological effects of T3, that are substantially different from those of Toc, may contribute to the antiatherogenic properties of T3.

Anti-inflammatory γ- and δ-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats.

Wong, W.Y., et.al (2017). Eur J Nutr

This study tested the hypothesis that γ- and δ-tocotrienols are more effective than α-tocotrienol and α-tocopherol in attenuating the signs of diet-induced metabolic syndrome in rats. In rats, δ-tocotrienol improved inflammation, heart structure and function, and liver structure and function, while γ-tocotrienol produced more modest improvements, with minimal changes with α-tocotrienol and α-tocopherol. The most important mechanism of action is likely to be reduction in organ inflammation.

Atheroprotective effects of pure tocotrienol supplementation in the treatment of rabbits with experimentally induced early and established atherosclerosis.

Rahman, T. A., et.al (2016). Food Nutr Res.

The atheroprotective properties of T3 in early and established atherosclerosis rabbits is established. These findings suggest the possible atheroprotective role T3 plays as an adjunct supplementation to standard treatment in the prevention of coronary artery disease.

Tocotrienol-Rich Tocomin Attenuates Oxidative Stress and Improves Endothelium-Dependent Relaxation in Aortae from Rats Fed a High-Fat Western Diet.

Ali, S.F., et.al (2016). Front Cardiovasc Med.

The role of whether Tocomin treatment (natural palm mixed-tocotrienol complex) preserves endothelial function in aortae isolated from rats fed a high-fat diet known to cause oxidative stress was investigated. The beneficial actions of tocomin in this diet-induced model of obesity suggest that it may have potential to be used as a therapeutic agent to prevent vascular disease in obesity.

Effects of Late Administration of Pentoxifylline and Tocotrienols in an Image-Guided Rat Model of Localized Heart Irradiation

Sridharan, V., et.al (2013). PLoS One.

This study examined the effects of pentoxifylline (PTX) alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation.

Palm Tocotrienol-Rich Fraction Improves Vascular Proatherosclerotic Changes in Hyperhomocysteinemic Rats

Norsidah, K-Z., et.al (2013). Evid Based Complement Alternat Med.

This study investigated the effects of palm tocotrienol-rich fraction (TRF) on aortic proatherosclerotic changes in rats fed with a high methionine diet. Palm TRF was comparable to folate in reducing high methionine diet-induced plasma hyperhomocysteinemia, aortic oxidative stress, and inflammatory changes in rats.

Suppression of nitric oxide production and cardiovascular risk factors in healthy seniors and hypercholesterolemic subjects by a combination of polyphenols and vitamains

Qureshi, A.A, et.al (2012). J Clin Exp Cardiolog.

To determine whether serum nitric oxide (NO) levels increase with age in humans, and whether the combined cholesterol-lowering and inflammation-reducing properties of resveratrol, pterostilbene, Morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid would reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes. Serum NO levels are elevated in elderly humans compared to children or young adults. Diet supplementation with combinations of resveratrol, pterostilbene, morin hydrate, quercetin, δ-tocotrienol, riboflavin, and nicotinic acid reduce cardiovascular risk factors in humans when used as nutritional supplements with, or without, other dietary changes.

δ-Tocotrienol and quercetin reduce serum levels of nitric oxide and lipid parameters in female chickens

Qureshi, A.A., et.al (2011). Lipids Health Dis.

Chronic, low-grade inflammation provides a link between normal ageing and the pathogenesis of age-related diseases. A series of in vitro tests confirmed the strong anti-inflammatory activities of known inhibitors of NF-κB activation (δ-tocotrienol, quercetin, riboflavin, (-) Corey lactone, amiloride, and dexamethasone). δ-Tocotrienol also suppresses β-hydroxy-β-methylglutaryl coenzyme A (HMG-CoA) reductase activity (the rate-limiting step in de novo cholesterol synthesis), and concomitantly lowers serum total and LDL cholesterol levels. We evaluated these compounds in an avian model anticipating that a dietary additive combining δ-tocotrienol with quercetin, riboflavin, (-) Corey lactone, amiloride, or dexamethasone would yield greater reductions in serum levels of total cholesterol, LDL-cholesterol and inflammatory markers (tumor necrosis factor-α [TNF-α], and nitric oxide [NO]), than that attained with the individual compounds.

Tocotrienol enriched palm oil prevents atherosclerosis through modulating the activities of peroxisome proliferators-activated receptors.

Li, F. et.al (2010). Atherosclerosis.

Palm oil is enriched in vitamin E in the form of alpha-, gamma-, and delta-tocotrienols. Dietary tocotrienol supplements have been shown to prevent atherosclerosis development in patients and preclinical animal models. However, the mechanistic basis for this health beneficial effect is not well established. Peroxisome proliferator-activated receptors alpha, gamma, and delta (PPARalpha, PPARgamma, and PPARdelta) are ligand regulated transcription factors that play essential preventive roles in the development of atherosclerosis through regulating energy metabolism and inflammation. In this study, we presented data that the tocotrienol rich fraction (TRF) of palm oil activated PPARalpha, PPARgamma, and PPARdelta in reporter based assays. Importantly, TRF attenuated the development of atherosclerosis in ApoE-/- mice through inducing PPAR target gene liver X receptor alpha (LXRalpha) and its down-stream target genes apolipoproteins and cholesterol transporters, suggesting that modulating the activities of PPARs is a key aspect of the in vivo action of tocotrienols.

Comparative study of the effect of tocotrienols and tocopherols on fasting serum lipid profiles in patients with mild hypercholesterolaemia: A preliminary report.

Ajuluchukwu, J.N., et.al (2007). Niger Postgrad Med. J

This study examines the effects of tocotrienols on serum lipids. This study adds to existing evidence of the favorable effect of tocotrienols on total cholesterol and LDL-C. However, the results need further clarification.

Proposed mechanisms of red palm oil induced cardioprotection in a model of hyperlipidaemia in rat

Esterhuyse. J.S., et.al (2006). Prostaglandins Leukot Essent Fatty Acids.

The effects of dietary red palm oil (RPO) containing fatty acids, carotonoids, tocopherols and tocotrienols on myocardial ischaemic tolerance and NO-cGMP pathway function in the rat. Wistar rats were fed a standard rat chow+/-RPO, or a standard rat chow+cholesterol+/-RPO diet. These data suggest that dietary RPO may improve myocardial ischaemic tolerance by increasing bioavailability of NO and improving NO-cGMP signaling in the heart.

Dose-response impact of various tocotrienols on serum lipid parameters in 5-week old female chickens.

Yu, S.G., et.al (2006). Lipids.

The cholesterol-suppressive action of the tocotrienol-rich-fraction (TRF) of palm oil may be due to the effect of its constituent tocotrienols on beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase activity. The tocotrienols, modulate HMG-CoA reductase activity via a post-transcriptional mechanism. As a consequence small doses (5-200 ppm) of TRF-supplemented diets fed to experimental animals lower serum cholesterol levels. Alpha-Tocopherol did not affect total or LDL-cholesterol levels. Supplemental alpha-tocotrienol within the 50-500 ppm range produced a dose-response lowering of total (17%) and LDL (33%) cholesterol levels. The more potent gamma and delta isomers yielded dose-response (50-2,000 ppm) reductions of serum total (32%) and LDL (66%) cholesterol levels. HDL cholesterol levels were minimally impacted by the tocotrienols; as a result, the HDL/LDL cholesterol ratios were markedly improved (123-150%) by the supplements. Serum triglyceride levels were significantly lower in sera of pullets receiving the higher supplements. The safe dose of various tocotrienols for human consumption might be 200-1000 mg/d based on this study.

Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes

Samarjit, D., et.al (2005). APS Journals.

The present study was designed to determine whether tocotrienol has a direct cardioprotective role. The results of this study support a role for c-Src in postischemic cardiac injury and dysfunction and demonstrate direct cardioprotective effects of TRF. The cardioprotective properties of TRF appear to be due to inhibition of c-Src activation and proteasome stabilization.

Hypolipidemic and antioxidant properties of tocotrienol rich fraction isolated from rice bran oil in experimentally induced hyperlipidemic rats.

Minhajuddin, M., et.al (2005). Food Chem Toxicol.

A dose-dependent hypolipidemic and antioxidant effect of tocotrienol rich fraction (TRF) isolated from rice bran oil on experimentally induced hyperlipidemic rats was investigated. These results suggest that TRF supplementation has significant health benefits through the modulation of physiological functions that include various atherogenic lipid profiles and antioxidants in hypercholesterolemia.

Suppression of 7,12-dimethylbenz[alpha]anthracene-induced carcinogenesis and hypercholesterolaemia in rats by tocotrienol-rich fraction isolated from rice bran oil.

Iqbal, J., et.al (2003). Eur J Cancer Prev.

The anti-tumour and anti-cholesterol impacts of tocotrienol-rich fraction (TRF) were investigated in rats treated with the chemical carcinogen 7,12-dimethylbenz [alpha]anthracene (DMBA), which is known to induce mammary carcinogenesis and hypercholesterolaemia. Results indicate that TRF has potent anti-cancer and anti-cholesterol effects in rats.

Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters.

Raederstorff, D., et.al (2002). Ann Nutr Metab.

The effects of a 4-week dietary supplement of either gamma-tocotrienol (86% gamma-T3) or a mixture of tocotrienols (29.5% alpha-T3, 3.3% beta-T3, 41.4% gamma-T3, 0.1% delta-T3: mix-T3) on the plasma lipid profile in hamsters receiving a high fat diet were investigated. This study provides further evidence that tocotrienols lower total cholesterol and low density lipoprotein plasma levels in hamsters and that gamma-tocotrienol is a more potent agent than a mixture of tocotrienols.

Dose-dependent cholesterolemic activity of tocotrienols.

Khor, H. et.al (2002). J Nutr.

The effect of tocotrienols and alpha-tocopherol on the activities of HMG CoA reductase and cholesterol 7 a-hydroxylase was investigated. Our results showed that the effects of tocotrienols and a-tocopherol on the activities of both the enzymes were dose-dependent. At low dosages, both tocotrienols and a-tocopherol exhibited an inhibitory effect on both the enzymes. Moreover, tocotrienols were a much stronger inhibitors than a-tocopherol. At high dosages, on the other hand, tocotrienols and a-tocopherol showed opposite effects on the enzymes. While tocotrienols continued to exhibit an inhibitory effect, a-tocopherol actually exhibited a stimulatory effect on both the enzymes. A possible explanation for this observation is suggested.

The combined effects of novel tocotrienols and lovastatin on lipid metabolism in chickens.

Qureshi & Peterson (2001). Atheroschlerosis.

Both lovastatin (a fungal product) and a tocotrienol rich fraction (TRF(25), a mixture of tocols isolated from stabilized and heated rice bran containing desmethyl [d-P(21)-T3] and didesmethyl [d-P(25)-T3] tocotrienols) are potent hypocholesterolemic agents, although they suppress cholesterol biosynthesis by different mechanisms. To determine additive and/or synergistic effects of both agents, chickens were fed diets supplemented with 50 ppm TRF(25) or d-P(25)-T3 in combination with 50 ppm lovastatin for 4 weeks. The effects, however, of the d-P(25)-T3/lovastatin combination were no greater than that of d-P(25)-T3 alone, possibly indicating that d-P(25)-T3 produced a maximum cholesterol lowering effect at the concentration used.

Novel Tocotrienols of Rice Bran Suppress Cholesterogenesis in Hereditary Hypercholesterolemic Swine

Qureshi, A.A., et.al (2001). Am Society for Nutritional Sc.

The effects of novel tocotrienols on lipid metabolism in swine expressing hereditary hypercholesterolemia is evaluated. This persistent effect may have resulted from the high tocotrienol levels in blood of the treatment groups, suggesting that the conversion of tocotrienols to tocopherols may not be as rapid as was reported in chickens and humans.

Tocotrienols Regulate Cholesterol Production in Mammalian Cells bv Post-transcriptional Suppression of 3-Hydroxy-3-methylglutarylCoenzyme A Reductase

Parker, R.A., et.al (1993). J of Biol Chem.

Tocotrienols are natural farnesylated analogues of tocopherols which decrease hepatic cholesterol production and reduce plasma cholesterol levels in animals. For several cultured cell types, incubation with y-tocotrienol inhibited the rate of [‘%]acetate but not mevalonate incorporation into cholesterol in a concentration- and time-dependent manner, with 50% inhibition at -2 HM and maximum -80% inhibition observed within 6 h in HepG2 cells. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase total activity and protein levels assayed by Western blot were reduced concomitantly with the decrease in cholesterol synthesis. In HepG2 cells, y-tocotrienol suppressed reductase despite strong blockade by inhibitors at several steps in the pathway, suggesting that isoprenoid flux is not required for the regulatory effect. HMG-CoA reductase protein synthesis rate was moderately diminished (67% of control), while the degradation rate was increased 2.4-fold versus control (t1,2 declined from 3.73 to 1.59 h) as judged by [3SS]methionine pulse-chase/immunoprecipitation analysis of HepG2 cells treated with 10 PM y-tocotrienol. Under these conditions, the decrease in reductase protein levels greatly exceeded the minor decrease in mRNA (23 versus 76% of control, respectively), and the low density lipoprotein receptor protein was augmented. In contrast, 25-hydroxycholesterol strongly cosuppressed HMG-CoA reductase protein and mRNA levels and the low density lipoprotein receptor protein. Thus, tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMG-CoA reductase, and appear to specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative non-sterol isoprenoid regulators derived from mevalonate.

Tocotrienol and fatty acid composition of barley oil and their effects on lipid metabolism.

Wang, L., et.al (1993). Plant Foods Hum Nutr.

Barley oil was extracted with hexane from the grain of a high oil waxy hull-less barley. Twelve male broiler chicks were fed corn-based diets with either 10% barley oil, 10% corn oil or 10% margarine ad libitum for ten days. These data suggest that alpha-tocotrienol and polyunsaturated fatty acids are hypocholesterolemic components in barley oil.

Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias.

Qureshi, A.A., et.al (1991). Am J Clin Nutr.

Normolipemic and genetically hypercholesterolemic pigs of defined lipoprotein genotype were fed a standard diet supplemented with 50 micrograms/g tocotrienol-rich fraction (TRF) isolated from palm oil. Hypercholesterolemic pigs fed the TRF supplement showed a 44% decrease in total serum cholesterol, a 60% decrease in low-density-lipoprotein (LDL)-cholesterol, and significant decreases in levels of apolipoprotein B (26%), thromboxane-B2 (41%), and platelet factor 4 (PF4; 29%). The declines in thromboxane B2 and PF4 suggest that TRF has a marked protective effect on the endothelium and platelet aggregation. The effect of the lipid-lowering diet persisted only in the hypercholesterolemic swine after 8 wk feeding of the control diet. These results support observations from previous studies on lowering plasma cholesterol in animals by tocotrienols, which are naturally occurring compounds in grain and palm oils and may have some effect on lowering plasma cholesterol in humans.

*In-vitro* Studies
Article	Study Objectives/ Findings
γ-Tocotrienol reduces human airway smooth muscle cell proliferation and migration. Harada, T., et.al (2015). Pulm Pharmacol Ther.	The effect of tocotrienol on human airway smooth muscle (ASM) cell growth and migration, both of which mediate airway remodeling in asthma is examined. γ-Tocotrienol could impart therapeutic benefits for airway remodeling in asthma by inhibiting human ASM cell proliferation and migration.

In-vitro Studies

Article

Study Objectives/ Findings

γ-Tocotrienol reduces human airway smooth muscle cell proliferation and migration.

Harada, T., et.al (2015). Pulm Pharmacol Ther.

The effect of tocotrienol on human airway smooth muscle (ASM) cell growth and migration, both of which mediate airway remodeling in asthma is examined. γ-Tocotrienol could impart therapeutic benefits for airway remodeling in asthma by inhibiting human ASM cell proliferation and migration.

Review Article
Article	Study Objectives/ Findings
Tocotrienol is a cardioprotective agent against ageing-associated cardiovascular disease and its associated morbidities Ramanathan et.al., (2018). Nutrition & Metabolism	Ageing is a nonmodifiable risk factor that is linked to increased likelihood of cardiovascular morbidities. Whilst many pharmacological interventions currently exist to treat many of these disorders such as statins for hypercholesterolemia or beta-blockers for hypertension, the elderly appear to present a greater likelihood of suffering non-related side effects such as increased risk of developing new onset type 2 diabetes (NODM). In some cases, lower efficacy in the elderly have also been reported. Alternative forms of treatment have been sought to address these issues, and there has been a growing interest in looking at herbal remedies or plant-based natural compounds. Oxidative stress and inflammation are implicated in the manifestation of ageing-related cardiovascular disease. Thus, it is natural that a compound that possesses both antioxidative and anti-inflammatory bioactivities would be considered. This review article examines the potential of tocotrienols, a class of Vitamin E compounds with proven superior antioxidative and anti-inflammatory activity compared to tocopherols (the other class of Vitamin E compounds), in ameliorating ageing-related cardiovascular diseases and its associated morbidities. In particular, the potential of tocotrienols in improving inflammaging, dyslipidemia and mitochondrial dysfunction in ageing-related cardiovascular diseases are discussed.
Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits Shahidi, F., et.al (2016). Int J Mol Sci.	Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible oils with considerable contents of tocopherols and tocotrienols. Tocopherols are among the most important lipid-soluble antioxidants in food as well as in human and animal tissues. Tocopherols are found in lipid-rich regions of cells (e.g., mitochondrial membranes), fat depots, and lipoproteins such as low-density lipoprotein cholesterol. Their health benefits may also be explained by regulation of gene expression, signal transduction, and modulation of cell functions. Potential health benefits of tocols include prevention of certain types of cancer, heart disease, and other chronic ailments. Although deficiencies of tocopherol are uncommon, a continuous intake from common and novel dietary sources of tocopherols and tocotrienols is advantageous. Thus, this contribution will focus on the relevant literature on common and emerging edible oils as a source of tocols. Potential application and health effects as well as the impact of new cultivars as sources of edible oils and their processing discards are presented. Future trends and drawbacks are also briefly covered.
Red palm oil: nutritional, physiological and therapeutic roles in improving human wellbeing and quality of life. Oguntibeju, O. O., et.al (2009). Br J Biomed Sci.	The link between dietary fats and cardiovascular disease has created a growing interest in dietary red palm oil research. Also, the link between nutrition and health, oxidative stress and the severity or progression of disease has stimulated further interest in the potential role of red palm oil (a natural antioxidant product) to improve oxidative status by reducing oxidative stress in patients with cardiovascular disease, cancer and other chronic diseases. In spite of its level of saturated fatty acid content (50%), red palm oil has not been found to promote atherosclerosis and/or arterial thrombosis. This is probably due to the ratio of its saturated fatty acid to unsaturated fatty acid content and its high concentration of antioxidants such as beta-carotene, tocotrienols, tocopherols and vitamin E. It has also been reported that the consumption of red palm oil reduces the level of endogenous cholesterol, and this seems to be due to the presence of the tocotrienols and the peculiar isomeric position of its fatty acids. The benefits of red palm oil to health include a reduction in the risk of arterial thrombosis and/or atherosclerosis, inhibition of endogenous cholesterol biosynthesis, platelet aggregation, a reduction in oxidative stress and a reduction in blood pressure. It has also been shown that dietary red palm oil, taken in moderation in animals and humans, promotes the efficient utilisation of nutrients, activates hepatic drug metabolising enzymes, facilitates the haemoglobinisation of red blood cells and improves immune function. This review provides a comprehensive overview of the nutritional, physiological and biochemical roles of red palm oil in improving wellbeing and quality of life.

Review Article

Article

Study Objectives/ Findings

Tocotrienol is a cardioprotective agent against ageing-associated cardiovascular disease and its associated morbidities

Ramanathan et.al., (2018). Nutrition & Metabolism

Ageing is a nonmodifiable risk factor that is linked to increased likelihood of cardiovascular morbidities. Whilst many pharmacological interventions currently exist to treat many of these disorders such as statins for hypercholesterolemia or beta-blockers for hypertension, the elderly appear to present a greater likelihood of suffering non-related side effects such as increased risk of developing new onset type 2 diabetes (NODM). In some cases, lower efficacy in the elderly have also been reported. Alternative forms of treatment have been sought to address these issues, and there has been a growing interest in looking at herbal remedies or plant-based natural compounds. Oxidative stress and inflammation are implicated in the manifestation of ageing-related cardiovascular disease. Thus, it is natural that a compound that possesses both antioxidative and anti-inflammatory bioactivities would be considered. This review article examines the potential of tocotrienols, a class of Vitamin E compounds with proven superior antioxidative and anti-inflammatory activity compared to tocopherols (the other class of Vitamin E compounds), in ameliorating ageing-related cardiovascular diseases and its associated morbidities. In particular, the potential of tocotrienols in improving inflammaging, dyslipidemia and mitochondrial dysfunction in ageing-related cardiovascular diseases are discussed.

Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits

Shahidi, F., et.al (2016). Int J Mol Sci.

Edible oils are the major natural dietary sources of tocopherols and tocotrienols, collectively known as tocols. Plant foods with low lipid content usually have negligible quantities of tocols. However, seeds and other plant food processing by-products may serve as alternative sources of edible oils with considerable contents of tocopherols and tocotrienols. Tocopherols are among the most important lipid-soluble antioxidants in food as well as in human and animal tissues. Tocopherols are found in lipid-rich regions of cells (e.g., mitochondrial membranes), fat depots, and lipoproteins such as low-density lipoprotein cholesterol. Their health benefits may also be explained by regulation of gene expression, signal transduction, and modulation of cell functions. Potential health benefits of tocols include prevention of certain types of cancer, heart disease, and other chronic ailments. Although deficiencies of tocopherol are uncommon, a continuous intake from common and novel dietary sources of tocopherols and tocotrienols is advantageous. Thus, this contribution will focus on the relevant literature on common and emerging edible oils as a source of tocols. Potential application and health effects as well as the impact of new cultivars as sources of edible oils and their processing discards are presented. Future trends and drawbacks are also briefly covered.

Red palm oil: nutritional, physiological and therapeutic roles in improving human wellbeing and quality of life.

Oguntibeju, O. O., et.al (2009). Br J Biomed Sci.

The link between dietary fats and cardiovascular disease has created a growing interest in dietary red palm oil research. Also, the link between nutrition and health, oxidative stress and the severity or progression of disease has stimulated further interest in the potential role of red palm oil (a natural antioxidant product) to improve oxidative status by reducing oxidative stress in patients with cardiovascular disease, cancer and other chronic diseases. In spite of its level of saturated fatty acid content (50%), red palm oil has not been found to promote atherosclerosis and/or arterial thrombosis. This is probably due to the ratio of its saturated fatty acid to unsaturated fatty acid content and its high concentration of antioxidants such as beta-carotene, tocotrienols, tocopherols and vitamin E. It has also been reported that the consumption of red palm oil reduces the level of endogenous cholesterol, and this seems to be due to the presence of the tocotrienols and the peculiar isomeric position of its fatty acids. The benefits of red palm oil to health include a reduction in the risk of arterial thrombosis and/or atherosclerosis, inhibition of endogenous cholesterol biosynthesis, platelet aggregation, a reduction in oxidative stress and a reduction in blood pressure. It has also been shown that dietary red palm oil, taken in moderation in animals and humans, promotes the efficient utilisation of nutrients, activates hepatic drug metabolising enzymes, facilitates the haemoglobinisation of red blood cells and improves immune function. This review provides a comprehensive overview of the nutritional, physiological and biochemical roles of red palm oil in improving wellbeing and quality of life.